The experimental program will be directed toward a better understanding of physiologic and metabolic mechanisms underlying the development and long-term maintenance of normal neuromuscular relationships. Having established that our cord-muscle cultures provided a reliable model system of organotypic neuromuscular development, the cultures will be used to explore basic relationships within and between CNS and muscle explants. Trophic influences of neurons and supporting cells on the maturation of muscle fibers and vice versa will be investigated prior to the formation and in direct relation to the neuromuscular junction. The cultures will be exposed to experimental conditions designed to impair or interrupt normal functional nerve muscle interrelationships without causing overt damage to either of these components. Coordinated cytologic, histochemical, electrophysiologic and electronmicroscopic studies will be made on cord- muscle cultures following application of selective pharmacologic agents, e.g. anticholinergic drugs, local anesthetics and other neural depressants, as well as agents affecting axoplasmic transport and mitochondrial function. The functional competence of anterior horn cells may be altered through microsurgical lesions of specific regions of the neural complex. Attempts will also be made to examine factors which may mimic neurotrophic influence on muscle and prevent or retard muscle atrophy after denervation, e.g. sympathetic and CNS neurons, neural tissue extracts and specific chemical agents, and directly induced muscle contractions.